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The Journal of Emergency Medicine, Vol. 40, No. 3, pp. 291–295, 2011Copyright © 2011 Elsevier Inc.

Printed in the USA. All rights reserved0736-4679/$–see front matter

doi:10.1016/j.jemermed.2008.10.015

Selected Topics:Toxicology

TARKA® (TRANDOLAPRIL/VERAPAMIL HYDROCHLORIDE EXTENDED-RELEASE)OVERDOSE

Victor Cohen, BS (PHARM), PHARMD, BCPS, CGP,*† Samantha P. Jellinek, PHARMD,† Lydia Fancher, PHARMD,†Geetanjli Sangwan, MD,‡ Menachem Wakslak, MD,‡ Elizabeth Marquart* and Cyrus Farahani, MD*

*Department of Emergency Medicine, †Department of Pharmaceutical Services, and ‡Department of Medicine, Maimonides MedicalCenter, Brooklyn, New York

Reprint Address: Victor Cohen, BS (PHARM), PHARMD, BCPS, CGP, Department of Emergency Medicine, Department of Pharmaceutical

Services, Maimonides Medical Center, 4802 Tenth Avenue, Brooklyn, NY 11219

e Abstract—Background: Patients with fixed-dose com-bination product overdoses involving verapamil andtrandolapril may present differently than sole calciumchannel blocker (CCB) or angiotensin-converting en-zyme inhibitor (ACE-I) overdose alone, and may haveimplications for the toxicological management. TheACE-I component may confound the traditional responseto antidotal and supportive therapy recommended forCCB overdoses. In such cases, it may be prudent tomanage the trandolapril component concurrently whileadministering traditional CCB antidotes. Objectives: Toreport a probable case and review the toxicological man-agement of a fixed-dose antihypertensive combinationproduct toxicity involving verapamil and trandolapril(Tarka®). Case Report: A 60-year-old man experienceddizziness and fell after ingesting five tablets of Tarka®.Eight hours later, he was found to be hypotensive andbradycardic. Therapy for CCB toxicity was initiated,including fluids, modified hyperglycemia-euglycemia in-sulin therapy, calcium chloride, activated charcoal, andglucagon. The patient’s blood pressure and heart ratestabilized only after the administration and titration ofdopamine and episodes of profuse vomiting in responseto glucagon. The patient was transferred to the CardiacIntensive Care Unit for further monitoring. He was con-sidered stable to the point of all therapies being discon-tinued only 12 h post-ingestion. The patient was dis-charged 40 h after ingestion with no further sequelae.Conclusions: Lack of familiarity with the components offixed-dose combination products poses a problem during

RECEIVED: 5 May 2008; FINAL SUBMISSION RECEIVED: 25 J

CCEPTED: 8 October 2008

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overdose situations and may confound the presentationand delay resuscitation and acute stabilization. © 2011Elsevier Inc.

e Keywords—Tarka®; overdose; fixed-dose combina-tions; calcium channel blocker; angiotensin-converting en-zyme inhibitor

INTRODUCTION

Fixed-dose combination products for the treatment ofessential hypertension are becoming increasingly pre-valent. Currently, there are more than 20 combinationproducts available on the market (1). Four of these pro-ducts contain angiotensin-converting enzyme inhibitors(ACE-I) or angiotensin receptor blockers (ARB) andcalcium channel blockers (CCB). These products includeTarka® (trandolapril/verapamil hydrochloride extended-release (ER); Tarka-Abbott Laboratories, Abbott Park,IL), Exforge® (amlodipine/valsartan; Exforge-Novartis,East Hanover, NJ), Lexxel® (enalapril maleate/felodip-ine; Lexxel-AstraZeneca, Wilmington, DE) and Lotrel®(amlodipine besylate/benazapril hydrochloride; Lotrel-Novartis Pharmaceuticals, Suffern, NY). Fixed-dosecombination products have many benefits over mono-therapy, including being more effective than the sum ofthe effectiveness of either product alone; they must be at

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292 V. Cohen et al.

least equally safe relative to the safety of either productused alone and the risk/benefit ratio of the combinationproduct must be lower than that of either product alone (2).

ixed-dose combination products also reduce non-compli-nce to medication regimens by 24–26% compared toonotherapy (3). Disadvantages include lack of flexibilityith dose administration for its individual components, lackf familiarity of the individual components of fixed-doseombination products among practitioners, and a lack ofata on the clinical presentation and management of fixed-ose combinations in the overdose setting (4).

The purpose of this report is to describe the toxico-ogical manifestations and management of a case of axed-dose antihypertensive combination overdose involv-

ng Tarka®, a product composed of the slow-releaseormulation of the CCB, verapamil, and the immediate-elease ACE-I, trandolapril. As we experienced, toxici-ies involving fixed-dose combination products includingCB and ACE-I may present a conundrum for the emer-ency physician.

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Glucagon 3 mg IVP

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Figure 1. Management of Tarka® overdose and blood press

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CASE REPORT

60-year-old man (weight 107 kg, height 5=4�) presentedo the Emergency Department (ED) with a chief complaintf dizziness. At 9:30 p.m. the previous evening, approxi-ately 8 h before presentation, he had mistakenly ingestedve tablets of his prescribed medication, Tarka®, instead ofis usual regimen of vitamins and natural supplements.pon realizing the mistake, he induced emesis. Throughout

he night he became increasingly dizzy and collapsed whenrying to stand. No loss of consciousness was reported. Hisedical history included hypertension, arthritis, asthma,

on-insulin-dependent diabetes mellitus, and hyperlipid-mia. His surgical history included cardiac catheterizationnd right knee replacement. His home medications includedspirin 81mg daily, clopidogrel 75 mg daily, zafirlukast 10g daily, and trandolapril/verapamil ER 4–240 mg daily.The toxicological course and responsiveness to emer-

ency care interventions is depicted in Figure 1. Uponrrival at the ED at 6:00 a.m., the patient was hypoten-

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sive with a blood pressure of 61/35 mm Hg, and brady-cardic with a heart rate of 52 beats/min. The review ofsystems was significant for fatigue and dizziness. Thephysical examination revealed a fatigued-appearing,obese, calm and cooperative, alert and oriented man whowas bradycardic, with a weak dorsalis pedis pulse and anintact radial pulse. Procedures for acute stabilizationwere instituted, including the administration of a liter of0.9% sodium chloride intravenously. In several commu-nications with the poison control center, calcium chloride500 mg by intravenous piggyback and glucagon 3 mg byintravenous push were recommended as management forthe CCB overdose. Additionally, hyperinsulinemia/eug-lycemia therapy (HIET), which included 50 mL of dex-trose 50% followed by a 1-unit/kg bolus of regularinsulin (107 units) and a 1-unit/kg/h (107 units/h) intra-venous infusion of regular insulin, was recommended.

The clinicians debated whether to give such a highdose of insulin as they were concerned about the risk ofadverse outcomes and the need for intensive monitoring.Due to these concerns, at 6:10 a.m. the clinicians decidedto administer the calcium chloride and glucagon as rec-ommended, as well as a reduced dose of insulin in part,giving 0.05 units/kg (6 units) as a bolus and 0.05 units/kg/h (6 units/h) of regular insulin as a continuous infu-ion titrated to effect. At 6:45 a.m., in the midst ofeceiving approximately 250 mg of a 500-mg calciumhloride infusion, the patient vomited and the calciumhloride infusion was discontinued.

The patient remained hypotensive, with a blood pres-ure of 65/32 mm Hg, and bradycardic, with a heart ratef 42 beats/min. After the administration of glucagon 3g intravenous push at 7:00 a.m., the blood pressure

ncreased to 72/44 mm Hg and the heart rate to 48eats/min. Within minutes the patient again becameildly nauseous. Due to the slight clinical response to

lucagon, at 8:45 a.m., a second bolus dose of glucagonmg intravenous push followed by an intravenous infu-

ion of 4 mg/h was administered. At this time, a 1-gramnfusion of calcium gluconate was also initiated. Further,ecause gastric decontamination procedures were not yetnstituted, 100 grams of activated charcoal was admin-stered in an attempt to adsorb the slow-release formu-ation of verapamil.

After ingesting significant amounts of activated char-oal, the patient began to vomit profusely, temporallyelated to the administration of the glucagon or perhapsue to the toxin itself. Despite this, the patient remainedypotensive, with a blood pressure of 75/44 mm Hg, andas still bradycardic with a heart rate of 44 beats/min.he patient experienced several more episodes of vom-

ting, and the glucagon infusion was titrated down to 2g/h followed soon after by discontinuation of the in-

usion altogether. At this time, although the patient a

remained hypotensive, his blood pressure did increase to80/34 mm Hg. He remained bradycardic, with a heartrate of 51 beats/min. Because the patient was not toler-ating the glucagon, at 9:30 a.m. a dopamine infusion wasinitiated at 5 �g/kg/min and titrated to response. Thepatient’s blood pressure increased to 86/46 mm Hg, andhis heart rate was 50 beats/min.

As the patient was recovering from the vomitingepisodes, at 10:30 a.m. he was transferred to the CardiacIntensive Care Unit (CICU) for further management.Upon arrival in the CICU at 2:00 p.m., both the insulinand dopamine infusions were discontinued. The patient’sblood pressure was 116/66 mm Hg, with a heart rate of55 beats/min, at approximately 17 h post-ingestion. Hissymptoms of dizziness abated. He was continuouslymonitored with hourly checks of vital signs and serialelectrocardiograms, which revealed sinus bradycardiawith a right bundle-branch block (present before thishospitalization). With the exception of Tarka®, all homemedications were restarted the following morning. Thepatient was discharged approximately 40 h after inges-tion of the Tarka® overdose with no sequelae.

DISCUSSION

Based on the Naranjo adverse drug reaction probabilityscale, this verapamil and trandolapril combination product-induced hypotension and bradycardia was considered prob-able and secondary to the accidental ingestion of multipletablets of the fixed-dose combination product, Tarka® (5).

o rechallenge was conducted and plasma drug concentra-ions were not available to confirm the toxicity.

Practitioner knowledge of the content of fixed dose-ombination products is limited. Biron conducted a piloturvey of 60 physicians, assessing their knowledge of theumber and names of the active ingredients found in 23xed-dose combination products they had prescribed in the

ast year (6). The percentage of correct answers in this studyanged from 0–66% (median 20%). Knowledge was in-ersely proportional to the number of ingredients containedn the combination. Hemminki et al. interviewed 102 phy-icians, assessing their knowledge of the generic names ofhe active ingredients found in five fixed-dose combinationroducts; they found that only 11% of physicians were ableo correctly identify all of the generic names (7). Fourteenercent of physicians who had prescribed the drugs withinhe previous 6 months were able to identify all of theeneric names. Thirty-three percent of all of the physiciansho were interviewed were able to describe the indicationr pharmacological group, but did not mention that morehan one drug was included in the product, and 19% ofhysicians were not able to give any correct information

bout the product. Theoretically, this lack of knowledge has

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294 V. Cohen et al.

the potential to impact the toxicological manifestations andmanagement of fixed-dose combination products.

Published reports on the toxicological manifestations ofthe fixed dose combination products differ from whatwould be expected with either CCB or ACE-I overdosesalone. Gokel et al. report on 2 patients who presented withacute renal failure with rhabdomyolysis and thromboticmicroangiopathy (TMA) 10 and 4 h, respectively, afteradministration of the fixed-dose combination. Only one ofthe patients presented with the classic presentation of hy-potension and bradycardia (8,9). Batalis et al. described anunusual case of verapamil-trandolapril toxicity (10). Theatient was found unresponsive approximately 12 h afterarka® overdose, and subsequently expired. Toxicology

eports completed at autopsy supported a lethal verapamilevel of 6000 ng/mL, and contributory comorbid conditionsuch as renal failure that may have delayed the eliminationf both components.

Our patient presented with hypotension and bradycar-ia approximately 8 h after ingestion, with elevatedlood urea nitrogen and serum creatinine, suggesting aisk of delayed verapamil and trandolapril eliminationnd, potentially, a prolonged risk for morbidity. No ev-dence of TMA syndrome was evident from laboratoryalues with the exception of mild elevations of creatinehosphokinase and myoglobin. From the few publishedeports of fixed-dose combination overdoses involvingerapamil and trandolapril, clinicians providing emer-ency care must consider the clinical presentation foroth components individually, as the combination mayot only produce synergistic toxic effects but each com-onent may also have independent hazards distinct fromach other.

There are numerous cases of ACE-I overdose reportedn the literature, suggesting that the ACE-I componentay confound the traditional response to the recom-ended CCB antidotal therapy (HIET, glucagon, cal-

ium chloride) due to similar clinical manifestations thatccur via different mechanisms (11–14).

ACE-I toxicity patients typically present with hypo-ension and a relative bradycardia. Non-cardiac symp-oms that have been reported include lethargy, tiredness,nd impaired consciousness (15). Treatment should in-lude fluid resuscitation and vasopressors. Naloxone alsoay be effective in reversing the hypotensive effects ofCE-I. Intravascular volume replacement with crystal-

oid or colloid solutions is the recommended initial treat-ent for ACE-I overdose (15). The presence of renal

nsufficiency or the danger of fluid overload may pre-lude its use in certain situations. Profound hypotensionay require the use of inotropes such as norepinephrine,

pinephrine, dopamine, or dobutamine. Naloxone admin-stration at doses of up to 10 mg given as an intravenous

olus both with and without an infusion of 0.04 mg/min b

as been attempted, with equivocal results (11). Nalox-ne seems to block endogenous �-endorphins responsi-

ble for inhibiting the centrally mediated activity of an-giotensin II. ACE-I block the enzyme, enkephalinase,which is involved in the breakdown of endogenous�-endorphins, contributing to the drug’s hypotensive ef-ect. Trandolaprilat, the active metabolite of trandolapril,esponsible for its ACE-I activity, is removed by hemo-ialysis, and that may be an effective treatment option.ew options for the toxicological management of theCE-I component exist or are readily available, with the

xception of supportive measures such as fluids andressors, which are also a part of the CCB toxicityanagement algorithm. In the case reported here, pres-

ors fell lower on the CCB toxicity management list thanlucagon, calcium, and HIET, antidotes to which theCE-I component is not likely to respond. Perhaps in thenique case of the fixed-dose combination therapies,ressors should be administered early and concurrentlyith other treatments for the CCB toxicity component.HIET protocols requiring the administration of 50%

extrose and large doses of intravenous short-acting insulin0.5–1 unit/kg) followed by a maintenance infusion (initi-ted at 0.5 units/kg/h and titrated to 2 units/kg/h) andupplemental intravenous potassium and dextrose haveeen used anecdotally as treatment for circulatory shockrom CCB poisoning (16). HIET therapy is believed tomprove inotropy and peripheral vascular resistance duringhock by improving carbohydrate uptake used by myocytesnd smooth muscle for energy (17). Case reports supportingts use suggest that a peak inotropic response is seen after0–15 min when high-dose insulin is employed and after5–60 min when submaximal doses are administered (18).dverse events associated with HIET include hypoglyce-ia and hypokalemia. Capillary glucose should be moni-

ored every 20 min for the first hour. Serum potassium andapillary glucose should be checked hourly, making this aabor-intensive and challenging antidote in overcrowdedDs. The insulin infusion may be tapered off once signs ofardiotoxicity begin to resolve (19). Before institutingIET, the significance of the ingestion as well as the

bility of the support staff to monitor the patient must beonsidered, as lack of continuity may result in a potentialor morbidity.

Guidelines for CCB overdose prepared by Boyer et al.uggest that HIET should be reserved for patients withverdose refractory to fluid resuscitation, high-dose cal-ium, and vasopressors (17,20). Thus, it may be prematureo recommend this therapy, as it may promote a drugisadventure instead of its intended goal of supporting

esuscitation. The lack of well-designed, human-controlledlinical trials demonstrating efficacy and lack of toxicityreclude its first-line use in the setting of fixed-dose com-

ination overdose involving CCB and ACE-I. Furthermore,

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Tarka® Overdose 295

HIET’s role in reversing the cardiovascular effects seenwith the ACE-I overdose has not been studied.

The successful use of low-dose HIET therapy hasbeen reported in the literature and this has lead to the useof low-dose HIET therapy (21,22). However, our patientdid not respond to low-dose HIET therapy and ultimatelyrequired the administration of other supportive measures.

CONCLUSIONS

ack of familiarity with the components of fixed-dose com-ination products poses a problem during overdose situa-ions and may confound the presentation and delay optimalreatment. We propose that for fixed-dose combinationroduct toxicity involving ACE-I and CCB, pressors shoulde initiated earlier in the course of treatment so that theCE-I component is treated concurrently with the CCB

oxicity component. Data are needed to assess the impact ofIET for fixed-dose combination product toxicity in the

etting of the ED, where continuity of care and aggressiveonitoring may not always be possible.

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